High cholesterol inhibits tendon-related gene expressions in tendon-derived stem cells through reactive oxygen species-activated nuclear factor-κB signaling.

Abstract

Clinical studies have indicated that increased serum cholesterol levels raised the risk of tendinopathy in hypercholesterolemia, but the effect of cholesterol on tendon-derived stem cells (TDSCs) and its underlying mechanism have not been studied. The purpose of this study is to investigate the association between cholesterol and tendinopathy in vitro and in vivo, and its underlying molecular mechanism as well. In TDSCs, the effect of cholesterol was assessed by quantitative polymerase chain reaction, western blot analysis, and immunofluorescence staining. Intracellular levels of reactive oxygen species (ROS) was detected, using flow cytometry. The link between nuclear factor (NF)-κB signaling and the effect of cholesterol was evaluated using a representative IκB kinase (IKK) inhibitor, BAY 11-7082. In addition, Achilles tendons from apolipoprotein E mice fed with a high-fat diet were histologically assessed using hematoxylin and eosin staining and immunohistochemistry. We found that high cholesterol apparently lowered the expression of tendon cell markers (collagen 1, scleraxis, tenomodulin), and elevated ROS levels via the NF-κB pathway both in vitro and in vivo. The ROS scavenger N-acetylcysteine (NAC) and BAY 11-7082 reversed the inhibiting effect of cholesterol on the tendon-related gene expressions of TDSCs. Moreover, NAC blocked cholesterol-induced phosphorylation of IκBα and p65. Significant histological alternation in vivo was shown in Achilles tendon in the hypercholesterolemic group. These results indicated that high cholesterol may inhibit the tendon-related gene expressions in TDSCs via ROS-activated NF-кB signaling, implying pathogenesis of tendinopathy in hypercholesterolemia and suggesting a new mechanism underlying hypercholesterolemia-induced tendinopathy.

• Authors: Kaiqun Li, Ganming Deng, Ye Deng, Siwei Chen, Hangtian Wu, Caiyu Cheng, Xianrong Zhang, Bin Yu, Kairui Zhang
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 10 Pg. 18017-18028 (08 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 30825206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Antioxidants
• NF-kappa B
• Reactive Oxygen Species
• Cholesterol

Topics

• Achilles Tendon (drug effects, metabolism, pathology)
• Animals
• Antioxidants (pharmacology)
• Cells, Cultured
• Cholesterol (metabolism)
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Hypercholesterolemia (drug therapy, genetics, metabolism, pathology)
• Male
• Mice, Knockout, ApoE
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Stem Cells (drug effects, metabolism, pathology)
• Tendinopathy (genetics, metabolism, pathology, prevention & control)